Pharmaceutical product for endonasal administration for treating central nervous system disease and disorders

ABSTRACT

The invention concerns a pharmaceutical product consisting of one or more standard active substances and/or of one or more standard metabolites acting on the central nervous system. Said active substances are added with substances acting on the nasal mucous membrane for endonasal administration.

The invention relates to a pharmaceutical product with active agentsaffecting the central nervous system, with an added active substanceacting on the nasal mucous membrane for endonasal administration.

The therapeutic use of oxygen radicals and/or their reaction orbreakdown products is known. For example, the use of O₂ ^(•-) for thetreatment of bronchial asthma is known (N. Goldstein et al., AdjuvanteInhalationstherapie des Asthma bronchial emit exogenem Superoxid(Adjuvant inhalation therapy of bronchial asthma with exogenicperoxide); Phys. Rehab. Kur. Med. 7,1997,138-140). It is also known thatinhalation of gas phase peroxide or hydrogen peroxide in lowconcentrations enhances the analgesic effect of analgesics administeredenterally or parenterally or intraperoneally, as described by Goldsteinet al. (see Goldstein et al.: Exogenous gaseous superoxide potentiatesthe antinociceptive effect of opioid analgesic agents, Inflamm. Res.,45, 1996, 473-478), and known from DE 195 14 522. It is also known fromDE 197 08 643 to use gaseous superoxide or hydrogen peroxide for atherapeutic administration with Morbus Parkinson.

One of the main possible methods for treatment and regulation of thefunctions of the organism of mammals is a direct stimulation or effecton the limbic and reticular system of the brain by affecting thehypothalamus. The hypothalamus is an important part of the brain,responsible for controlling the internal environment and maintaining thehomeostasis of the organism.

Integrative functions of the hypothalamus include vegetative, somaticand hormonal reactions of the organism, in particular control of theactivity of endocrinal and exocrinal glands, control of the sleep/wakestate, sensation of pain, sensation of thirst and hunger, hormonalcontrol, emotional reactions and the like. The particularities of thestructure and function of the hypothalamus make it the target foradequate and non-invasive, non-traumatic treatment methods and foraffecting different defective functions of the organism.

Special neurons of the hypothalamus have chemo-receptor functions andare sensitive to changes of physiologically important parameters in theblood and the cerebrospinal fluid. They are therefore capable ofreceiving information signals from the interior of the organism and fromthe environment. The information signals from the interior environmentof the organism are transmitted through simple metabolites, for exampleby amino acids, carbohydrates, peptides, nucleotides. Hormones and theirderivates, mediators and/or neuro-transmitters and other natural andartificial regulators also participate in the transmission of thesesignals.

The information signals from the environment, for example from inhaledair, are sensed by the hypothalamus through the exterior receptors ofthe nasal cavity and cause corresponding reactions of the organism. Thehypothalamus is therefore a suitable point of attack for drugs andmetabolic molecules for controlling physiological effects.

Unlike enteral or parenteral methods for the administration of drugs,the endonasal administration can be advantageous due to thesignificantly smaller concentrations and doses compared to the commonlyused concentrations and doses. These advantages include primarily areduction of toxic effects and of side effects. Another importantadvantage of the nasal administration of drugs is the non-invasivecharacter.

However, DE 195 14 522 C1 describes potentiation of analgesics only inthe context of SAR (oxygen ion radicals), relating exclusively to aseparate administration of SAR (i/nasal) and analgesics (i/p and per os,respectively); moreover, the analgesic was not applied intranasally. Thepractical administration of these products is complicated, because theyare based on two consecutive administrations, namely SAR and analgesics,and only moderately enhance the analgesic effect, whereas thetherapeutic intranasal administration of SAR in treatment of MorbusParkinson is surprisingly effective.

DE 693 21 458 T2 describes the administration of products that promoteabsorption. However, this relates to a form of an enhancedadministration, but not to potentiation of the efficacy of particulartypes of analgesics. Only polar metabolites, such as glucoronides, ofopioid analgesics were used for the therapeutic administration of opioidanalgesics, which are supposed to have a greater efficacy compared tothe base materials (morphine, codeine, levorphanol, etc.). The analgesiceffect should develop at a concentration of morphine-6-glucoronide of0.15 mg/kg bodyweight.

Only polar metabolites of opioid analgesics are described fortherapeutic use which, however, are not suitable per se for generatingan analgesic effect with morphine. Moreover, the drug form of ananalgesic should only be prepared in connection withabsorption-enhancing substances made of a cationic polymer, abio-adhesive material, a surface-active material, a fatty acid, ahelenate former, a mucus-dissolving substance, a cyclodextrin or amicrosphere preparation.

Finally, DE 690 17 690 T2 describes administering, but not potentiatingthe efficacy of different drug preparations or metabolites. Thecompositions include absorption enhancers, namely surface-activesubstances, of a non-ionic type and of bile salt derivates and a drug,such as insulin or calcitonin.

Attempts of a direct endonasal administration of drugs are alsodescribed in the published literature. For example, the endonasalintroduction of 6-glucoronide of morphine for reducing the side effectsof the drug is known (Illum L. et al., 1996, Biopharm Drug Dispos.,17(8): 717-724).

Another example describes the endonasal administration of bromocriptinin an attempt to reduce the side effects on the gastrointestinal tract(Cicinelli E. et al., 1996, J. Endocrinol. Invest. 19(7): 427-432).

The hypothalamus is a suitable point of attack for endonasally applieddrugs for affecting the central nervous system, as described for exampleby Illum L. et al. (1996), and Bechgaard E. et al. (J. Pharmacol., 1997,49 (8): 747-750). In addition, RU-PS 2 149 043 describes a method fortreating cerebral angiodystonia by endonasal administration of anaerosol containing lituitrin.

In a number of cases, natural hormones and their synthetic analoguesand/or derivates are also used endonasally. For example, estrens areknown which indirectly affect the hypothalamus. The administration ofsteroids is described in patent WO 9610032, authors: D. Berliner et al.,for example 1,3,5 (10)-16-estratetraen-3-ol, which can stimulate theneuro-epithelial receptors of the nasal mucous membrane and can beintroduced through the nasal cavity of the recipients. Also known is theendonasal administration of norpregnan for controlling sexual behavior.

A significant deficiency of the aforedescribed drugs for endonasaladministration that can also affect the central nervous system is theirunsatisfactory healing efficacy. The reason for the low efficacy ofprior art endonasally applied drugs may be caused by the inadequatesensibility of the receptor structures of the target organs, inparticular the cores of the hypothalamus and other structures of thebrain, or in the high threshold for stimulating the affected receptors.Endonasally applied drugs that affect the central nervous system havetherefore only rarely been used.

It is an object of the present invention to increase the efficacy ofdrugs, metabolites and/or other reactive agents of the aforedescribedtype that can be used for treating disorders of the central nervoussystem, to significantly reduce the normally used dosage, and to achievea faster, prolonged activity.

The object is solved by administering a combined composition offree-radical products with biologically active ingredients forpotentiating the efficacy, whereby potentiation is achieved incombination with oxygen anion radicals (SAR) and/or nitrogenoxide-active products.

With these measures, subsequently abbreviated as NSAS, a pharmaceuticalsubstance is produced, which can be used to initially sensitize themucosa membrane of a patient. It is then possible to use differentsubstances, including metabolites. The increased efficacy is not onlyproduced in combination with SAR, but also with NO-active products. Onlya combined composition of free-radical products with biologically activesubstances is administered. The administration becomes much simpler inpractice, and a significantly higher analgesic effect is achieved withthe same dosage, or the same effects are achieved with a significantlylower dosage of analgesics.

It is also possible to administer pharmaceutically effective substances,which are typically administered in form of cabinets, drops, injectionand the like, as a nasal spray or a nasal ointment. The pharmaceuticallyeffective substances can therefore be administered in a significantlysmaller dosage, achieving nevertheless the same effect as with thecurrent higher doses.

In one embodiment, the NSAS oxygen radicals and/or their reaction ordecomposition products, namely perhydroxyl radicals, can be hydrogenperoxide, hydro-peroxide radicals or their hydrate clusters, and thesubstances active in the nasal mucus membrane can be forms of nitrogenmono-oxide (NO) and their precursors or reaction products.

Additional advantageous measures are described in the dependent claims.The invention will now be described in more detail.

It was unexpectedly discovered that by adding so-called vaso- or NSAS todrugs acting on the central nervous system, a significant increase inthe efficacy of the respective drug can be achieved, if the drug and theNSAS are applied in form of a mixture.

Included in the term vasoactive substances or substances that act on thenasal mucosa membrane according to the invention are in particular theoxygen radicals or radical formers O₂ ^(•-), H₂O₂, —O₂H, their hydrateclusters and also singlet oxygen ¹O₂, namely vasoactive forms of NO andbiochemical substances, such as arginin, bradykinin, urea, which have asimilar physiological effects in the context of the invention.

It is significant for the invention that the oxygen anion radicals areapplied simultaneously with the drug in form of an endonasal appliedmixture, preferably in liquid form.

Because of their metastable state, the oxygen anion radicals and/ornitrogen oxide are mixed with the respective drug immediately beforeadministration of the pharmaceutical composition.

The oxygen anion radicals of the present invention can be formed bychemical or enzyme generation, for example by xanthine oxidase(Fridovich, I., (1970), “Quantitative aspects of the production ofsuperoxide anion radical by milk xanthine oxidase,” J. Biol. Chem. 245,4053). The oxygen anion radicals can also be generated by physicalprocesses, for example with a superoxide generator (Inventor: Goldstein,N., Patent DE 195 12 228, 1995).

The NO-products of the present invention can be formed by chemical orenzyme generation, for example by NO synthesis.

In one embodiment, an aqueous solution of the respective drug is mixedimmediately before administration with a corresponding quantity of a10⁻⁵ mole/l H₂O₂ solution. The mixture is subsequently administered inform of a nasal spray or in another form. The volume of a single dose ofthe nasal spray is between 50 and 500 μl of a solution or a mixture ofthe drug and oxygen radicals as vasoactive substances.

The volume of a single dose of the nasal spray is preferably 100-200 μl.The concentration of the hydrogen peroxide in this dose is between 10⁻¹²mole/l and 10⁻¹ mole/l, preferably 10⁻⁸ mole/1 to 10⁻² mole/l, and mostpreferably 10⁻⁵ mole/l. The absolute quantity of the drug in the singledose is 0.0001 to 100 mg, preferably 0.1-10 mg.

In another embodiment, a mixture of xanthine oxidase and xanthine isused as a source for the oxygen anion radicals. A solution of xanthineoxidase and xanthine having a corresponding activity or concentration ismixed directly before administration with a solution of the respectivedrug. The volume of a single dose of the nasal spray is between 50 and500 μl of a solution or a mixture of drug and xanthine/xanthine oxidase.

Preferably, the volume of a single dose of the nasal spray is 200 μl.The concentration of xanthine oxidase is here between the 0.01 mg/ml and10 mg/ml, preferably between the 0.05 mg/ml, and most preferred betweenthe 0.1 mg/ml and 1 mg/ml. The concentration of xanthine is between the0.1 mg/ml and 100 mg/ml, preferably between 1 mg/ml and 50 mg/ml, andmost preferred between 5 mg/ml and 25 mg/ml. The absolute quantity ofthe drug in a single dose is 0.0001 mg to 100 mg, preferably 10 mg.

Due to the large number of individual parameters in the treatment ofdiseases of the central nervous system (individual pharmacokinetics ofthe drug, cause for the disorder, etc.), exact information about thetypical dosage of the corresponding drug can preferably be made based oncomparative values obtained on a single individual.

The novel effect, which forms the basis for the present invention, isinter alia a synergistic therapeutic effect between vasoactivesubstances, for example oxygen anion radicals and/or their reaction orbreakdown products, and the administered drug in a common intranasaladministration, so that the dose for achieving a defined effect can bereduced by at least 50%.

To achieve the synergistic effect according to the invention, forexample, the drugs promedol, metamizol, phenobarbital, dermorphin,dopamine, methadone, tramadol, Viagra™, or clonidin can be used.

The following examples demonstrate the novel enhanced efficacy of thecombination of these vasoactive substances, for example oxygen anionradicals and nitrogen radicals with corresponding medication accordingto the present invention. Regulatory and therapeutic effects on thecorresponding functions of healthy and sick organisms of animals and/orhumans were investigated.

EXAMPLE 1

The following experiments with rats show that with an endonasaladministration of the composition of H₂O₂ in a concentration of 10⁻⁵mole/i (3.4*10⁻⁴ mg/kg bodyweight) and glucose in a dose of 20 mg (i.e.,100 mg/kg bodyweight), the test animals showed a significantly reducedmotivation for food. The experiments where carried out with white malerats. The animals of the control group 1 (n=13) received distilledwater, the animals of the control group 2 (n=7) received a glucosesolution, and the animals of the experimental group (n=9) received thecomposition H₂O₂+glucose. The duration of the observation was 17 days.During the first 11 days, the animals where controllably partiallydeprived of food (20 g dry mixed feed per animal). During the first weekof the experiment, the initial motivation level for food was evaluatedin the absence of the investigated preparation. The following parameterswere investigated:

Latent period (LP) between the approach to the food and presentation ofthe food in seconds;

Time for consuming the food, in seconds (Tfut.);

Number of interruptions during food uptake (Ubr.)

After the second week, without changing the feed conditions, thepreparation was introduced twice daily in a dose of 20 μl per animal,and all parameters where recorded. After the second week, the animalswhere fed ad libidum. No changes were made in the administration of thepreparation and recordation of all parameters. The results of theinvestigation are listed in Tables 1 in 2. In these and other Tables,the results are shown as the average value±standard deviation. TABLE 1Parameters of the food motivation in the control group 1 and controlgroup 2 in comparison to the experimental group before and afteradministration of the preparation. Animal Before administration ofpreparation After administration of preparation groups LP [s] T_(fut.)[s] Ubr. [s] LP [s] T_(fut.) [s] Ubr. [s] Control group 1 76.9 ± 15.5419.0 ± 25.2 3.8 ± 0.4 42.2 ± 3.7 489.4 ± 3.7 3.9 ± 0.5 Intact animalsControl group 2 78.1 ± 14.3 421.6 ± 27.2 3.6 ± 0.5 48.1 ± 12.1 495.7 ±11.4 4.1 ± 0.4 Glucose endonasal Experiment 83.3 ± 13.9 417.2 ± 16.0 3.8± 0.4 73.1 ± 11.9**) 443.0 ± 17.8*) 3.7 ± 0.6 H₂O₂ + Glucose endonasal*)= p < 0.05; and**)= p < 0.001 as compared to control groups 1 and 2

TABLE 2 Changes in parameters of food motivation in the groups controlgroup 1, control group 2, and experiment. Test results beforeadministration of the preparation minus test results afteradministration of the preparation. Animal groups LP T_(fut.) Ubr.Control group 1 34.8 ± 16.0 −70.4 ± 27.2 −0.2 ± 0.8 Intact animalsControl group 2 30.0 ± 14.9 −74.1 ± 31.6 −0.5 ± 0.4 Glucose endonasalExperiment 10.2 ± 18.1 *) −25.8 ± 21.5   0.1 ± 0.7 H₂O₂ + Glucoseendonasal*) Significance p < 0.05 as compared to control groups 1 and 2

The results show that administration of the composition H₂O₂+glucose forfour days (twice daily) led to a significant prolongation of the latentperiod before approaching the food.

EXAMPLE 2

The experiments where conducted as in Example 1. The animals of thecontrol group 1 (n=13) received distilled water, the animals of thecontrol group 2 (n=6) received a glutamic acid solution, and the animalsof the experimental group (n=9) received the composition H₂O₂+glutamicacid (3.4*10⁻⁴ mg/kg bodyweight) and glutamic acid 10⁻³ mole/l, i.e.,1.74*10⁻² mg/kg bodyweight). The results are listed in Tables 3 and 4.TABLE 3 Parameters of the food motivation in the groups control group 1,control group II and experiment before and after administration of thecomposition H₂O₂ + glutamic acid. Animal Before administration ofpreparation After administration of preparation groups LP [s] T_(fut.)[s] Ubr. [s] LP [s] T_(fut.) [s] Ubr. [s] Control group 1 76.9 ± 15.5419.0 ± 25.2 3.8 ± 0.4 42.2 ± 3.7 489.4 ± 3.7 3.9 ± 0.5 Intact animalsControl group 2 69.9 ± 15.9 414.0 ± 30.6 4.1 ± 0.6 36.3 ± 4.1 491.2 ±9.4 3.7 ± 0.5 glutamic acid endonasal Experiment 45.6 ± 5.2 439.9 ± 5.24.8 ± 0.7 54.6 ± 10.0*) 413.2 ± 22.2**) 5.1 ± 0.6 H₂O₂ + glutamic acidendonasal*)Significance p < 0.05 and**)p < 0.01 as compared to control groups 1 and 2

TABLE 4 Changes in parameters of the food motivation in the groupscontrol group 1, control group II and experiment. Test beforeadministration of the administration minus test results afteradministration of the preparation. Animal groups LP [s] T_(fut.) [s]Ubr. [s] Control group 1 34.8 ± 16.0 −70.4 ± 27.2 −0.2 ± 0.8 Intactanimals Control group 2 33.3 ± 13.1 −77.2 ± 26.6   0.4 ± 0.6 glutamicacid endonasal Experiment −9.0 ± 12.4 *)   26.7 ± 17.2 **) −0.3 ± 0.7H₂O₂ + glutamic acid endonasal*) Significance p < 0.05 and **) p < 0.01 as compared to control group

The results have shown that administration of the compositionH₂O₂+glutamic acid resulted in a significant lengthening of the latentperiod for approaching the food and a decrease in the feeding time. Itis also evident that administration of oxygen radicals in the form ofH₂O₂ in a concentration of 10⁻⁵ mole/l and glutamic acid (10⁻³ mole/l)had an inhibiting effect on the food motivation in the test animals.

EXAMPLE 3

A placebo-controlled investigation was carried out on 6 volunteers.H₂O₂+glucose mixtures in concentrations of 6.8*10⁻⁷ mg H₂O₂ and 0.01 gglucose were administered endonasally 2-3 times daily.

The investigation was carried out on healthy male and female volunteerswith an increased body mass. The average age of the test persons was49.4±8.1 years for females and 52.2±5.8 years for males. The results forreducing the bodyweight are listed in Table 5. TABLE 5 Dynamics ofreducing the bodyweight in test persons (the mixed group, 4 females) asa result of endonasal administration of the composition H₂O₂ + glucosewith 6.8 * 10⁻⁷ mg H₂O₂ and 0.01 g glucose. Max. reduction in BodyweightBodyweight Bodyweight bodyweight [kg] [kg] [kg] (in % of Groups (Males +females) (Initial value) (after 14 days) (after 56 days) initial value)Administration of 89.6 ± 13.4 90.5 ± 14.3 90.1 ± 13.2 — placebo (n = 6)Administration of 91.8 ± 12.2 87.7 ± 12.9 78.5 ± 10.2 *)#) 15.5% thecomposition H₂O₂ + glucose (n = 6)*) Significance p < 0.05 as compared to placebo;#) Significance p < 0.05 as compared to initial body mass in therespective group

The results show that the administration of the H₂O₂/glucose mixture incomparison to the placebo results in a suppression of the appetite and aconsistent reduction in the bodyweight.

EXAMPLE 4

The anti-nociceptive and/or analgesic effect of promedol (trimeperidine)was investigated as a result of the endonasal administration of thecombination H₂O₂+promedol. The experiments were conducted with(raceless) sexually mature white male rats. In a pain test, the value ofthe critical pressure (WKD) on the rear paw of the rats was measured.The controlled pressure on the paw was generated with an analgesimeterfrom the company Ugo Basile in form of the Randall-Selitto test.

Comparative results in relation to the composition of the inventioninclude, on one hand, the intraperitoneal administration of promedolwithout the addition of oxygen anion radicals and, on the other hand,the intraperitoneal administration of promedol with addition of oxygenanion radicals by, on one hand, inhalation with the inhalation devicedescribed in DE 41 12 459 A1 and, on the other hand, by separateendonasal administration of a liquid hydrogen peroxide solution with aconcentration of 10⁻⁵ mole/l.

The administration according to the invention consisted of a mixture ofxanthine-oxidase/xanthine and promedol in doses of 5, 2, 1, and 0.1mg/kg bodyweight of the animals. The results are listed in Table 6:TABLE 6 Enhancement of the analgesic effect of promedol in a combinationwith oxygen radicals, here: Products of the xanthine-oxidase/xanthinereaction, as compared to intraperitoneal introduction of the analgesicwithout NSAS (groups II-IV) and to endonasal administration of NSAS(groups V-VII). Initial Time after injection or administration of valueof promedol, in minutes Animal groups nociception 30 90 150 210 I.Control group (n = 10) 7.2 ± 1.5  6.2 ± 1.2 5.7 ± 1.3 5.4 ± 1.0 5.4 ±1.1 II. Promedol, 1.0 mg/kg; 6.7 ± 0.9  6.2 ± 1.9 5.4 ± 1.4 5.0 ± 1.24.8 ± 0.9 i/p. (n = 10) III. Promedol, 2.0 mg/kg; 7.8 ± 1.6 10.1 ± 1.1*)9.3 ± 1.0*) 8.0 ± 1.1 7.5 ± 0.9 i/p. (n = 12) IV. Promedol, 5.0 mg/kg;6.4 ± 0.7 11.0 ± 1.0**) 9.8 ± 1.3**) 8.3 ± 1.7*) 6.7 ± 1.0 i/p. (n = 10)V. Promedol, 1.0 mg/kg; 6.9 ± 1.6  8.1 ± 3.6*) 8.1 ± 2.3**) 9.6 ± 5.0**)5.8 ± 2.3 i/p. + O₂ - inhalation (n = 10) VI. Promedol, 1.0 mg/kg; 7.1 ±1.8  8.4 ± 2.8*) 8.7 ± 2.0**) 8.6 ± 2.7**) 7.3 ± 2.2 i/p. + endonasalH₂O₂-administration (n = 10) VII. Combination 6.8 ± 1.6  8.7 ± 3.2**)9.2 ± 3.0**) 9.0 ± 2.9**) 8.8 ± 2.2**) promedol (0.1 mg/kg) + xanthine-oxidase/hypoxanthine, endonasal^(#)) (n = 12)Superoxide generation speed: 0.025 μM/min;applied total volume of H₂O₂: 440 μl (corresponds to 4 strokes of 110μl)*)Significance p < 0.05 and**)p < 0.01 as compared to the initial value in each defined group;^(#))xanthine-oxidase-activity 0.79 units/mg protein; concentration ofthe hypoxanthine 0.1 mM.

The results (group VII) listed in Table 6 show a more pronouncedincrease of the analgesic efficacy of the analgesic in a compositionwith oxygen anion radicals in the endonasal administration as comparedto the efficacy of promedol with parenteral introduction, as well aswith the separate effect of oxygen anion radicals (endonasal) and of theanalgesic (intraperitoneal). An increased efficacy of the endonasal formmanifests itself in a prolongation and enhancement of the analgesiceffect with a 10-50 times lower dose of the promedol as compared toother administration methods. The present experiments clearly show thatoxygen anion radicals in combination with promedol increase orsupra-additively enhance the potency of the analgesic effect of theanalgesic.

EXAMPLE 5

The enhancement of the therapeutic efficacy of the analgesic metamizolwas investigated. A total of 5 volunteers participated in theobservations. The preparation for endonasal administration consisted ofa combination of hydrogen peroxide (10⁻⁶ mole/l, corresponding to a doseof 6.8*10⁻⁷ mg) and metamizol (dose of 10 mg). The results aresummarized in Table 7. With all patients, the observations were madeafter six hours following the last administration of the pain therapy.TABLE 7 Results with one-time endonasal administration of H₂O₂ +metamizol in 5 patients with persistent or severe pain. Dose ofmetamizol 10 mg. Pain level Duration Patient Duration of (subjective,scale 0-5) of the (Name the illness, Before After effect, and age)Clinical diagnosis weeks administration administration hours 1. male,Posttraumatic 7 4 1 14 K-r, age headache 66 2. female Post herpetic 78 41 22 U-va, age facial pain 58 3. male, Pain after hand 1 day 5 1 6 R-v,age burns 39 4. female Post herpetic 48 4 0 17 P-ko, age facial pain 695. male, Posttraumatic 104 3 3 0 B-s, age headache 32 The basic nerveconnections between receptors of the nasal cavity and brain structureswere injured or damaged

The observations 1-4 confirm the efficacy of the methods in humans.Observation 5 (no effect) confirms the important role of the nasalcavity receptors in the efficacy of endonasal administration of drugs.This is the more surprising as the non-narcotic analgesic metamizol(Dipyron) is therapeutically not effective in a nasal administration. Inall patients, the administration of metamizol was not effective, neitherper os in a dose of 500 mg nor endonasally in a dose of 10 mg withoutthe addition of oxygen anion radicals. However, metamizol develops avery pronounced analgesic effect in combination with oxygen anionradicals.

EXAMPLE 6

The two following examples (Table 8) show the efficacy of endonasaladministration of the neurotransmitter dopamine in combination withdifferent vasoactive substances: L-arginine (as a biochemical source forthe nitrogen mono oxide NO), as well as hydrogen peroxide. It should beemphasized that dopamine is not capable of penetrating the blood-brainbarrier when administered conventionally. TABLE 8 Regeneration ofdamaged spontaneous activity through i/p administration of haloperidole(100 mg/kg bodyweight) in rats, caused by the onetime endonasaladministration of dopamine (0.025 mg corresponding to 0.125 mg/kgbodyweight) in combination with L-arginine (10⁻⁵ mole/l, correspondingto 1.75 * 10⁻⁴ mg/kg bodyweight) or H₂O₂ (10⁻⁶ mole/l, corresponding to3.4 * 10⁻⁶ mg/kg bodyweight). Total spontaneous activity (Number ofmeasurable Animal groups movements) I. Unharmed control (n = 7) 35 ± 8II. Haloperidol i/p (n = 9)  3 ± 3 ^(##)) III. Haloperidol i/p +Dopamine endonasal (n = 5)  2 ± 1.7 ^(##)) IV. Haloperidol i/p + H₂O₂endonasal (n = 5)  3 ± 1.9 ^(##)) V. Haloperidol i/p + H₂O₂ + Dopamineendonasal 38 ± 7 **⁾ (n = 7) VI. Haloperidol i/p + L-arginine + dopamine27 ± 6 **⁾ endonasal (n = 6)^(##)) Significance P II, III, IV vs. I < 0.01;**⁾ = P V, VI vs. II, III, IV < 0.01.

EXAMPLE 7

The therapeutic effect of endonasal administration of a mixture ofoxygen anion radicals and dopamine was observed on sick patients withthe clinical diagnosis of advanced stage Parkinson's disease (stages2.0-3.0 according to Hoehn & Yahr). A total of 3 volunteers participatedin the observations. The preparation for the endonasal administrationconsisted of a combination of hydrogen peroxide (10⁻⁷ mole/l) withdopamine (1 mg). All patients underwent regular standard therapy for thedisease until the day of the clinical observation. The results of theseobservations are summarized in Table 9. TABLE 9 Results of theobservations of the therapeutic effect with one-time administration ofthe preparation H₂O₂ + dopamine in patients with Parkinson's disease(change in the motor functions and expression). Tremor Rigor WalkPatient and be- be- be- Expression duration of fore after fore afterfore after before after illness treatment treatment treatment treatmentMale E-n, +++ +++ ++ +++ + +++ ++ ++ age 8 Male G-o, + +++ +++ +++ + +++++ ++++ age 3 Female, N- +++ +++ ++ +++ + ++ + +++ a, age 6The characters +, ++, +++, and ++++ indicate a very poor, poor, good,and excellent function.

DE-PS 197 08 643 describes a moderate therapeutic effect of endonasaladministration of superoxide or hydrogen peroxide in patients withtremors (Parkinson's disease). It was subsequently noted that thehealing effect of oxygen anion radicals is observed predominantly duringthe initial stage of the disease (stages 1.0-1.5 according to Hoehn &Yahr). It was also noted in DE 197 08 643 that the healing effect of theNSAS develops not before 10 to 20 days of treatment. With theadministration according to this invention, however, all patientsexperienced a positive healing effect within several minutes afteradministration, which can still be detected both subjectively andobjectively (by a physician) within 6 to 72 hours.

EXAMPLE 8

Female patient: age 61 years; clinical diagnosis: adynamic depressionwith mood swings. The basic clinical symptoms: apathy, remorse, concern,hostile behavior towards family members. Previous treatment:antidepressants amitriptiline, desipramine, maprotiline, as well askavasedon, etc. The drugs were administered irregularly due to poorcompatibility.

Because the condition continued to deteriorate, a compositionH₂O₂+tryptophan with concentrations of 0.1 mg tryptophan and 3.4*10⁻⁴ mgH₂O₂ was administered endonasally (as a spray). The spray wasadministered endonasally 2 times daily over two days, each time 200 μlin each nasal cavity.

Result: The female patient experienced subjectively an improvement inthe mental conditions 4 hours after the first administration. On thesecond and third day, apparent positive changes where noticedsubjectively and objectively (by a physician). All major clinicalsymptoms of the disease are practically in remission. The patientreported an improvement in her ability to work, an improvement in hermood, and a decline of negative emotions. One endonasal administrationper week was made during the course of a 3-week follow-up treatment. Theaforedescribed improved condition continued during the 30-dayobservation period, without any side effects.

EXAMPLE 9

The enhancement of the analgesic effect of dermorphine in combinationwith xanthine-oxidase/xanthine as compared to conventionalintraperitoneal and endonasal methods for the administration ofdermorphine was investigated (Table 11). The experiments were conductedwith raceless white male rats. The analgesic activity was investigatedby the tail flick reflex method. The reaction was recorded one hourafter administering the preparation. TABLE 11 Analgesic effectExperimental groups (in % for control) 1. Intraperitoneal administrationof 12.5 ± 4.2 dermorphin (0.05 mg/kg) 2. Endonasal administration ofdermorphin 26.2 ± 6.1 *) (0.05 mg/kg) 3. Endonasal administration ofdermorphin 46.9 ± 6.4 **) #) (0.005 mg/kg) in combination with xanthineoxidase/xanthineApplication volume: 20 μl*) Significance p 2 vs. 1 < 0.01;**) = p 3 vs. 1 < 0.01;#) = p 3 vs. 2 < 0.01.Enzymatic activity of xanthine oxidase/xanthine = 0.79 I.U./mg protein;concentration of xanthine = 0.1 mM.

The results show that the oxygen anion radical-forming mixturexanthine-oxidase/xanthine in combination with the oligopeptide 9DAFGYPS-NH2 (dermorphine) markedly enhances the antinociceptive(analgesic) effect of the analgesic with endonasal administration.

EXAMPLE 10

The administration of phenobarbital for the treatment of epilepsy isknown. Disadvantageously, however, this treatment has undesirable sideeffects, for example an increase in the P-450 activity in the liver anda modification of the metabolism of different drugs, as well as nausea,dizziness and the like. Phenobarbital is typically applied in a dose ofapproximately 100 mg.

Investigated was the effect of phenobarbital in an endonasaladministration on sexually mature white mice. Both the sedative and thesoporific effect of the endonasal administration of phenobarbitalwithout oxygen anion radicals were compared with the administration ofthe TABLE 12 Enhancement of the soporific effect of phenobarbital incombination with glucose-oxidase/glucose as compared to pure endonasaladministration of phenobarbital. Sleep Experimental groups duration(minutes) Control group phenobarbital endonasal 60 mg/ml 248.5 ± 22.2 (n= 7) Experimental group 369.8 ± 29.4 **) Glucose-oxidase/glucose +phenobarbital endonasal 5 mg/ml (n = 6)**) = p < 0.1.The enzymatic activity of glucose-oxidase = 0.66 I.U./mg;glucose concentration = 0.15 mM.

EXAMPLE 11

The prevention of an epileptic seizure in its initial stage wasinvestigated in a 19-year-old patient with the clinical diagnosisessential epilepsy. The symptoms, which preceded the attack, were:increased excitability, symptoms of tonic tension of the muscles,unintentional urination. The listed symptoms were always followed by anextensive epileptic seizure in this patient.

The patient was given twice within 3 minutes endonasal administrationscomposed of H₂O₂+phenobarbital. The effective doses of phenobarbitalwere always 10 mg.

Result: 3 minutes after the second administration of the composition,the symptoms of tonic tension of the muscles lessened, and the desire tourinate stopped. A moderate sleepiness developed. No epileptic seizureoccurred during the following three days.

EXAMPLE 12

It is known that the commonly used drugs, namely ergotamine,methylsergide, tricyclic antidepressants, karbamazepine, sumatriptane,etc., cause various side effects in migraine sufferers, for examplenausea, vomiting, dizziness, tremor, sleepiness, skin reactions, etc.

In the present example, clinical tests were performed for preventing thebeginning phase of migraine attacks in two female patients, age 36 and28 years, both with the clinical diagnosis of migraine.

The characteristic symptoms preceding the attack were: aura (onepatient), escalating unilateral headaches, and nausea. The listedsymptoms in these female patients always developed into a migraineattack.

The composition H₂O₂+phenobarbital was administered endonasally in thesepatients. The effective dose of phenobarbital in each case was 10 mg.

Result: Approximately 5 minutes after administration, most patientsreported a lessening of the listed symptoms of migraine attacks. Nofurther migraine attacks developed in these patients during thefollowing 72 hours.

1. Pharmaceutical product with active ingredients affecting the centralnervous system, with addition of a substance active in the nasal mucousmembrane for endonasal administration, wherein a combined composition offree radical products with biologically active substances areadministered for potentiating the efficacy, wherein the increasedefficacy occurs in combination with oxygen anion radicals (SAR) and/ornitrogen oxide active products.
 2. Pharmaceutical product according toclaim 1, wherein the potentiation is attained by drug-like substancesand different types of metabolites, and such substances of a chemicalnature.
 3. Pharmaceutical product according to claim 1, wherein thepotentiation is attained in conjunction with different types of freeradicals (SAR, NO-radicals) and/or corresponding radical formers. 4.Pharmaceutical product according to claim 1, wherein the substancesactive in the nasal mucous membrane are perhydroxyl radicals, hydrogenperoxide, hydroperoxide radicals or their hydrate clusters. 5.Pharmaceutical product according to claim 1, wherein the substancesactive in the nasal mucous membrane are forms of nitrogen monoxide (NO)and their precursors or reaction products.
 6. Pharmaceutical productaccording to claim 1, wherein the substances active in the nasal mucousmembrane are biochemical, physiological vaso-dilators, preferablyarginin, bradykinin, urea or eicosatric acid-derivates. 7.Pharmaceutical product according to claims 1, wherein utilizing amixture comprising substances active in the nasal mucous membrane in aconcentration of 10⁻¹² mole/l to 10⁻¹ mole/l.
 8. Pharmaceutical productaccording to claims 1, wherein utilizing a mixture comprising substancesactive in the nasal mucous membrane in a concentration of 10⁻⁵. 9.Pharmaceutical product according to claims 1 wherein conventional drugsubstances are included in a dose of 0.001 mg to 100 mg per dosage unit.10. Pharmaceutical product according to claims 1, wherein the metaboliteis included in a dose of 0.0001 mg to 100 mg per dosage unit. 11.Pharmaceutical product according to claims 1, wherein the drugsubstances are promedol, metamizol, phenobarbital, methadone, tramadol,ASS or sildenafil.
 12. Pharmaceutical product according to claim 1,wherein the metabolite is tryptophan, gamma-amino butyric acid,oxytocin, dermorphin, cyclic GMP, glucose, dopamine, or L-dopa. 13.Pharmaceutical product according to claims 1, wherein one or more of itsactive components are present in the composition as liposomes and/ornanosomes.
 14. Pharmaceutical product according to claims 1 wherein oneor more of its active components are present in the composition in aform different from the solution.
 15. Pharmaceutical product accordingto claims 1, wherein pharmaceutically acceptable, auxiliary substancesare present in the composition.
 16. Pharmaceutical product according toclaims 1, wherein the auxiliary substances are stabilizers,antioxidants, pH regulators, osmo-regulators or antimicrobialsubstances, which are present in the product in combination with apharmaceutical substance adequate for its administration. 17.Pharmaceutical product according to claims 1, wherein the product is aspray that can be endonasally administered.